Variant: NM_000527.5(LDLR):c.760C>T (p.Gln254Ter)

CA10585116

251436 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: c8ddc916-8f19-4334-ad28-b49e531f6f19

Approved on: 2022-08-28

Published on: 2022-08-28

HGVS expressions

NM_000527.5:c.760C>T
NM_000527.5(LDLR):c.760C>T (p.Gln254Ter)
NC_000019.10:g.11106630C>T
CM000681.2:g.11106630C>T
NC_000019.9:g.11217306C>T
CM000681.1:g.11217306C>T
NC_000019.8:g.11078306C>T
NG_009060.1:g.22250C>T
ENST00000558518.6:c.760C>T
ENST00000252444.9:n.1014C>T
ENST00000455727.6:c.314-762C>T
ENST00000535915.5:c.637C>T
ENST00000545707.5:c.379C>T
ENST00000557933.5:c.760C>T
ENST00000558013.5:c.760C>T
ENST00000558518.5:c.760C>T
ENST00000558528.1:n.275C>T
ENST00000560467.1:n.360C>T
NM_000527.4:c.760C>T
NM_001195798.1:c.760C>T
NM_001195799.1:c.637C>T
NM_001195800.1:c.314-762C>T
NM_001195803.1:c.379C>T
NM_001195798.2:c.760C>T
NM_001195799.2:c.637C>T
NM_001195800.2:c.314-762C>T
NM_001195803.2:c.379C>T

Pathogenic

• Met criteria codes: PVS1 PP4 PM2 PM3

• Not Met criteria codes: BA1 BP2 BP3 BP4 BP1 BP5 BP7 BS2 BS4 BS3 BS1 PP1 PP3 PP2 PM6 PS2 PS4 PS3 PS1 PM1 PM4 PM5

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PM2, PM3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - Variant leads to stop at codon 254. It is amino-terminal of amino acid 830, so PVS1 is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PM3 - variant meets PM2 and was identified in 1 index case (Patient F3) with LDLc 18.21 mmol/l and compound heterozygote with NM_000527.5(LDLR):c.1216C>A (p.Arg406=) from Du et al. 2016 (PMID: 28028493). -- 2nd variant is classified as Likely Pathogenic by these guidelines and patient has phenotype of homozygous FH, so PM3 is met. PP4 - variant meets PM2 and was identified in 1 index case with DLCN at least 14 (LDL of 18.21mmol/L and xanthomas), from Du et al. 2016 (PMID: 28028493), China, so PP4 is met.

Met criteria codes

• PVS1: Variant leads to stop at codon 254. It is amino-terminal of amino acid 830, so PVS1 is met
• PP4: variant meets PM2 and was identified in - 1 index case with DLCN at least 14 (LDL of 18.21mmol/L and xanthomas), from Du et al. 2016 (PMID: 28028493), China. so PP4 is met
• PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met
• PM3: variant meets PM2 and was identified in 1 index case (Patient F3) with LDLc 18.21 mmol/l and compound heterozygote with NM_000527.5(LDLR):c.1216C>A (p.Arg406=) from Du et al. 2016 (PMID: 28028493). -- 2nd variant is classified as Likely Pathogenic by these guidelines and patient has phenotype of homozygous FH, so PM3 is met

Not Met criteria codes

• BA1: This variant is absent from gnomAD (gnomAD v2.1.1).
• BP2: not identified in index cases with other variants and phenotype of heterozygous FH, so not met
• BP3: not applicable
• BP4: variant meets PVS1, so not applicable
• BP1: not applicable
• BP5: not applicable
• BP7: variant is nonsense, so not applicable
• BS2: variant was not identified in normolipidemic individuals, so not met
• BS4: no segregation data
• BS3: this variant was not studied in functional studies
• BS1: This variant is absent from gnomAD (gnomAD v2.1.1).
• PP1: no segregation data
• PP3: variant meets PVS1, so not applicable
• PP2: not applicable
• PM6: no de novo occurrence
• PS2: no de novo occurrence
• PS4: variant meets PM2 and was identified in - 1 index case with DLCN at least 14 (LDL of 18.21mmol/L and xanthomas), from Du et al. 2016 (PMID: 28028493), China. not enough, so not met
• PS3: this variant was not studied in functional studies
• PS1: variant is nonsense, so not applicable
• PM1: variant is nonsense, so not applicable
• PM4: variant is nonsense, so not applicable
• PM5: variant is nonsense, so not applicable